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Reasonable people can look at a study, look at the regulations, and draw
different conclusions.
THE REGULATORY OVERSIGHT OF
PEDIATRIC RESEARCH
Most research regulations include special requirements for studies involving
children. In the United States, the Common Rule governing research defines
four levels of riskiness in pediatric research studies, each of which is subject
to a different level of regulation and oversight. The lowest level of risk is
“minimal risk,” which is defined as “the probability and magnitude of
physical or psychological harm that is normally encountered in the daily
lives, or in the routine medical or psychological examination of health
children.”5 Studies that entail only minimal risk can be carried out, even if
they do not offer any prospect of direct benefit to the research subjects.
Unfortunately, the category of “minimal risk” is problematic because the
definition of minimal risk is somewhat vague. It does not specify, for
example, whether the risks of everyday life should be those encountered by
normal, healthy children growing up in safe homes and safe neighborhoods
or, instead, should be those of sick children or children living in less optimal
environments. The “normal daily lives” of sick children often include
invasive procedures and dangerous drugs. Furthermore, the daily life of a
child can be quite risky. Children are at risk of injury when they ride a bike,
play competitive sports, take ballet lessons, or climb trees, but these risks
seem different from those to which a child is exposed in a research study.
This vagueness creates variable interpretations by investigators and
institutional review boards (IRBs).6 Shah and colleagues showed that IRB
chairs vary in their assessment of whether a procedure is minimal risk. For
example, allergy skin testing was found by 23% of those surveyed to be
minimal risk, whereas 70% thought it was greater than minimal risk.
7
The second level of risk in the U.S. federal regulations is an even vaguer
category, “a minor increase over minimal risk.” Research with this level of
risk—and with no prospect of direct benefit to the research subjects—may
be approved only if the research is likely to yield knowledge that is of vital
importance to understand or ameliorate the child’s disorder or condition.
These greater-than-minimal risks should be commensurate with those in the
child’s actual or expected medical, dental, psychological, social, or
educational situations.
Russell and colleagues noted that, although there is some disagreement
about the exact boundaries of “minimal risk” or “minor increase over
minimal risk,” the disagreements focus on a narrow range of studies and tend
to be resolved in a conservative manner. They note, “It is never morally
acceptable to enroll a child in a study that involves significant pain when
there is no prospect of direct benefit to that child, even when that child is
already subjected to painful treatments/procedures as a part of a therapeutic
regimen.”
A third risk category is for studies that include the prospect of direct
benefit to the child. Such studies may entail higher risks if the potential
benefit is judged to balance out the risks. Because many studies involve new
drugs or innovative procedures, we often do not know the risks or the
benefits. The reason we are doing the study is to quantify the risks and
benefits.8 Thus, judgments about the relative risks and benefits are always
tentative and require constant monitoring as the study is proceeding.
The fourth risk category is the most complex. It is for studies that involve
more than a minor increase over minimal risk and no prospect of direct
benefit for the child, but that are judged to be so important, in terms of the
knowledge that they might yield that they ought, perhaps, to be conducted
anyway. IRBs cannot approve these studies, but if they decide that the studies
should be approved, they can ask the federal government to convene an
expert panel to review them. The expert panel can decide that such studies
should be permitted. They may also modify the protocol or the consent
process.
THE COMPLICATED CONCEPT OF
“ASSENT”
Children who are old enough (and neurocognitively capable) must give their
assent before they can be enrolled in research studies. Assent is a
complicated topic because assent is different from consent. William
Bartholome, a pediatrician who was a strong advocate for children’s right to
refuse to participate in research, broke assent down into four elements. First,
he said, the child must have “a developmentally appropriate understanding”
of the nature of the condition. Second, investigators must disclose the nature
of the proposed study, including what interventions it will involve. Third,
those seeking assent must assess the child’s understanding of the information
provided and the influences on the child’s evaluation of the situation. Finally,
investigators must solicit the child’s expression of willingness to
participate.9 These elements require subjective assessments of each child’s
capacities. Roth-Cline and colleagues point out that controversies arise about
two different aspects of assent. First, researchers have to judge how much
information to give. Too little will lead to decisions that are not well
informed. Too much can be cognitively and emotionally overwhelming. Then,
researchers must decide whether patients and parents understand the
information. For this, they must develop “methods for assessing both
children’s understanding of disclosed information and of the assent process
itself and what constitutes an effective, practical, and realistically applicable
decision-making model.”
10
We often fall short of the ideal of child assent. Unguru and colleagues
showed that many children who assent and are then enrolled in cancer
clinical trials do not understand basic aspects of the research (e.g., that there
might be added risk compared to standard treatments) and do not actually
feel that they were able to play a significant role in decision-making.11 The
process of obtaining assent before enrolling children in research studies is
difficult and often flawed.
A deeper problem with assent arises when parents and their children
disagree about whether the child should be enrolled in a research study. For
studies in which the anticipated benefit is thought to outweigh the risk—such
as clinical trials of cancer chemotherapy—the parents may claim the right to
override the child’s dissent. In such situations, two fundamental moral
principles clash: the research paradigm that protects children’s autonomybased right to refuse and the clinical paradigm in which the principle of
beneficence generally guides doctors’ and parents’ choices.
Not surprisingly, IRB chairs are as variable in their interpretations of
assent as they are in their interpretations of minimal risk. Whittle et al. found
that half of IRB chairs rely on the investigators’ judgments about when assent
must be sought; the other half had a required method for investigators to
determine whether obtaining assent was appropriate, most commonly based
on age, but the age cutoff for requiring investigators to obtain assent from the
child ranged from ages 5 years or younger to 10 years or older.
12
CONTROVERSIAL RESEARCH IN CHILDREN
There are many examples of the difficulties in following the current
regulations for pediatric research. This chapter briefly discusses four areas
of controversy: studies involving genetic testing, the enrollment of healthy
children in studies of sibling bone marrow donation, studies of the use of
hypothermia for neonates with asphyxia, and comparative effectiveness
research (CER).
GENETIC TESTING RESEARCH IN CHILDREN
Studies of genetic testing in children have been ethically controversial.
Controversies arose in different domains. Some focused on population-based
newborn screening programs and questions of whether the information that is
gained from testing is of direct benefit to the child. For example, screening
newborns for sickle cell disease was controversial when there was no
beneficial treatment that could be offered to newborns with the disease. Once
it became clear that prophylactic penicillin saved lives, the ethical
controversy receded and screening became widely accepted. This has
happened with many other newborn tests. However, controversy continues to
grow around many newborn screening tests that diagnose genetic diseases for
which there is no widely accepted beneficial treatment.
Some of the earliest debates arose with the advent of population-based
newborn screening for autosomal recessive conditions, such as sickle cell
disease or cystic fibrosis. Newborn screening is an unusual form of clinical
testing. In most states, it is mandated and done without parental consent.
Some states allow parents to opt-out, but most do not explicitly inform
parents of this right.13 Testing without consent is only possible when the
benefits of testing are so clear and the harms so egregious that it would not
be harmful to the child not to be tested and treated. When newborn screening
was first developed, tests targeted severe disorders that were relatively
prevalent and treatable.
The advent of new technology that made screening easier and less
expensive led to the expansion of screening panels that can include diseases
that are untreatable.14 Tests for such diseases were initiated before there was
any empirical assessment of long-term outcomes, harms, and benefits. But it
is difficult to study the harms and benefits of a screening program because, in
many cases, there is no treatment or the treatment itself is experimental.
In addition to population screening, genetic testing has also been used to
test for carriers of genetic disease in carefully selected high-risk populations.
Usually, people are selected for testing based on their race, ethnicity, and
family history. For example, screening for Tay-Sachs was originally carried
out in Ashkenazi Jewish communities and screening for sickle cell in people
of African descent. People responded to the results with differing emotions.
Studies of screening for Tay-Sachs,15 muscular dystrophy,16 cystic fibrosis,
17
and many other conditions reveal that such testing is predictably associated
with anxiety and guilt in some people, euphoria or relief in others.
The latest form of genetic testing is whole-genome sequencing (WGS) or
whole-exome sequencing. This type of testing raises a host of new issues.
These arise, in part, because it can be used for a variety of purposes and for
a variety of contexts. It can be used to diagnose symptomatic children whose
conditions have eluded diagnosis with standard testing. It can be used to
predict later-onset disease in healthy children. It can be used in population
screening to diagnose disease or detect carrier status. In each of these cases,
controversies arise because genome sequencing results are difficult to
interpret. Interpretation will get better only with further study, but studying
genome sequencing also requires some decisions about which results to
disclose and how to interpret those results.
A recent summary of the ethical issues in genome sequencing by Johnston
et al. made specific recommendations regarding such testing in different
contexts.18 In the clinical context, they recommended, whole-exome
sequencing or WGS may be used to assist in diagnosis of symptomatic
newborns. This should be done in a research context and only with parental
consent and with access to genetic counseling.
The benefits of sequencing in a clinical context are deemed to outweigh
the risks. For affected children and families who participate in these types of
genetic testing research, the benefits of this kind of research outweigh the
risks. It may yield an etiologic diagnosis that may inform future treatments
and reproductive decisions. However, there are concerns about the
psychological harms caused by the identification of a genetic condition.
19,20
Attitudes within the professional community are quite divided as to
whether or not genome sequencing, even for diagnosis, is valuable. On one
hand, WGS is a potentially powerful tool that could transform the way that
we diagnose disease and estimate prognosis. WGS may allow difficult
diagnoses to be made in a timely way that would be impossible to make
using any other diagnostic tools. Bieseker and colleagues, proponents of such
testing, note, “…some of these variants can be not only highly predictive of
disease but their return can enable life-saving treatment.”21 Green imagines
“the routine use of genomics for disease prevention.”
22
On the other hand, many are skeptical about WGS’s clinical benefit, in
part, because they fear that it generates too much information, making its
interpretation difficult, especially because it creates a very low signal-tonoise ratio.23 Bieseker and colleagues recognized the problems of
information overload, “A whole-genome or -exome result is overwhelming
for both the clinician and the patient…(because)…. variants from genome or
exome range from those that are extremely likely to cause disease to those
that are nearly certain to be benign, and every gradation between these two
extremes.”
23
Barrington is among the skeptics who worry that this vast amount of
information is not only of no clinical benefit, but actually harmful. He
worries that such testing might lead to ambiguous results that cause anxiety
but have no clinical benefit for the child. He concludes, “I certainly wouldn’t
have whole genome sequencing, nor accept it for my children.”
22
Careful studies of the ways in which doctors and parents use and react to
DNA-based sequencing and analysis might help resolve the debate about
whether such testing is perceived overall as helpful, harmful, or simply
expensive and irrelevant. However, the studies themselves raise many of the
same ethical questions as do the tests.
Any potential benefits from genetic testing research in childhood are
significantly tempered when the child will not develop disease until
adulthood. A commonly cited case is identification of children with a genetic
predisposition to breast cancer. Many professional societies recommend
deferring such testing and allowing the child to grow up and then make the
decision about testing for himself or herself.
24,25
Johnston et al. warned, however, that, given the state of knowledge in
2018, gene sequencing should not be used as a sole screen in state-sponsored
newborn screening programs. The reason was because, in that context, there
were too many false-positive and false-negative tests, and even more
ambiguous findings as a result of genomic variants of unknown significance.
Instead, the group recommended targeted testing for specific diseases, as is
done today with population-based newborn screening. In some cases,
genome sequencing can be used in conjunction with newborn screening to
confirm specific genomic variants as a cause of disease. Research in this
area will likely continue to be controversial for decades to come.
RESEARCH ON HEALTHY CHILDREN WHO DONATE
STEM CELLS TO SIBLINGS
Hematopoietic stem cell transplantation has become standard treatment for a
number of oncologic and hematologic illnesses. The human leukocyte antigen
(HLA)–matched children may be identified as potential stem cell donors for
these pediatric patients.26 It is difficult to evaluate the risks and benefits to a
child of donating bone marrow to a sibling because the benefits are
psychological and the risks are physical. Research regulations stipulate that
children can participate in research if the benefits of participating balance
the risks. A recent protocol made the questions even more complex.
Investigators proposed to give the donors granulocyte-macrophage colonystimulating factor (GM-CSF), a treatment generally thought to be safe but one
with potential long-term risks, in order to improve the likelihood of success
for the recipient.27 In 2008, the U.S. Food and Drug Administration (FDA)
Pediatric Advisory Committee’s Pediatric Ethics Subcommittee reviewed
this protocol and considered whether a third party should advocate for the
donor, whether parental discretion can credibly be based on assessment of
risk and benefit to the donor, and what implications the committee findings
would have on future research on healthy sibling stem cell donation. They
concluded that
1. The potential research represented more than minor increase over
minimal risk.
2. There were potential benefits, but these were indirect. They should not
be considered a benefit of research.
3. The protocol offered an opportunity to address a serious problem
affecting the health of children. Thus, potential donors would be
allowed to participate provided that they had no identifiable risk factors
for complications from GM-CSF administration, that an independent
third party was available as an advocate for the potential donor, that the
life-threatening nature of some of the potential risks (acute respiratory
distress syndrome and leukemia) were disclosed in the informed
consent document, and that “all things being equal, preference should go
to an older sibling donor.”
28
RESEARCH ON THERAPEUTIC HYPOTHERMIA FOR
PERINATAL HYPOXIC–ISCHEMIC ENCEPHALOPATHY
Research on therapeutic hypothermia for newborns with perinatal asphyxia
illustrates a variety of ethical issues. The earliest clinical trials of
hypothermia for babies with neonatal hypoxic–ischemic encephalopathy
(HIE) were conducted in the late 1990s. Gunn and colleagues in New
Zealand showed that hypothermia could be administered safely.29 A few
years later, Shankaran and colleagues drew on Gunn’s research and on
animal studies to suggest that a prospective randomized trial offered a
prospect of direct benefit to research participants.30 Over the next few years,
many such randomized trials were conducted. A 2007 meta-analysis of eight
randomized controlled trials involving 638 term infants concluded that
therapeutic hypothermia improved both survival and neurodevelopmental
outcomes.31 Some adverse effects of hypothermia included an increase in the
need for inotrope support of borderline significance and a significant
increase in thrombocytopenia.
At that point, the debate shifted. Initially, it had been about whether or not
a randomized trial would be ethically permissible because some thought the
risks were too high and the prospect of direct benefit too low. After studies
showed that hypothermia had benefits, some investigators wanted to refine
the treatment by continuing to test different protocols for hypothermia against
placebo. Others argued that hypothermia should be considered the standard
of care and that, in future studies, it would be unethical not to offer it to
patients in the control arm. The debate polarized the neonatal research
community. In 2005, the American Academy of Pediatrics Committee on the
Fetus and Newborn noted, “Therapeutic hypothermia is a promising therapy
that should be considered investigational until the short-term safety and
efficacy have been confirmed in the additional human trials underway. Longterm safety and efficacy remain to be defined.”32 Kirpalani and colleagues
similarly called for more studies before accepting therapeutic hypothermia as
an efficacious therapeutic modality.
33
Others, however, took a different view. Wilkinson and associates, writing
in 2007, noted, “We believe that the strength of the existing evidence
warrants careful consideration of whether the risks to participants involved
in continuing trials are justified.”34 The next year, Gunn and colleagues noted
that the evidence of benefit was strong enough so that practicing physicians,
in consultation with patients and families, should routinely use hypothermia
as a treatment for neonatal encephalopathy.
35
The debate about hypothermia illustrates the difficulty in reaching an
answer to two different questions. One is deciding when a clinical trial of an
innovative therapy is justifiable. For this, we have to extrapolate from animal
data or small pilot studies. The second question arises as evidence from such
trials accumulates. Then, we have to decide when further studies are no
longer necessary. For both questions, reasonable people—and reasonable
IRBs—can disagree.36 Such debates frequently arise around intensive care
interventions.
37
For all such studies, we need a careful assessment of risk and benefit and
then a laborious and often impossibly complex process of informed consent.
The problems in assessing risks and benefits and then conveying them in a
consent form led to a controversy about a comparative effectiveness study in
neonates.
STUDYING OUTCOMES AFTER USING DIFFERENT
TARGETS FOR OXYGEN SATURATION IN PREMATURE
BABIES
CER is done to ascertain which of two treatments that are in widespread use
is safer and more effective. It usually involves a prospective randomized
trial. In the early 2000s, there was genuine uncertainty among experts in
neonatology about the optimum level of oxygen saturation to target in
adjusting ventilators and oxygen concentrations for critically ill premature
babies.
Some prominent voices see CER as a disingenuous effort “to blur or
eliminate the distinctions between research and therapy, scientist and
physician, and subject and patient.”38 Proponents disagree and instead
believe that CER can be conceptually distinguished from what we might call
“innovative therapy research” (where a new treatment is compared against a
placebo or a standard-of-care practice).39 Debates about the ethical
appropriateness of CER, generally, and about the study of oxygen saturation
targets, in particular, highlight long-standing and fundamental tensions in the
conduct of human subject research.
Supplemental oxygen is uniquely toxic to premature babies, and yet it is
essential for their survival. Thus, they must be given some oxygen or they
die. But if they are given too much oxygen for too long, then they can end up
with brain damage, blindness, visual impairment, or chronic lung disease.
Thus, it has been crucial for neonatologists to discover just how much oxygen
to give to these fragile babies. But the research studies that would allow
them to test different approaches to oxygen therapy in different
subpopulations of babies are methodologically challenging and ethically
controversial.
In order for any prospective study to be ethically appropriate, there must
be uncertainty about the relative risks and benefits of the different treatments
being studied. If clinicians and investigators knew that one treatment was
better, there would be no scientific reason to do the study and it would be
unethical at the outset. The requirement for genuine uncertainty dictates, to a
certain extent, what must be included in the informed consent form and
discussion.
Parents need information about the potential harms and benefits of
enrolling their child in a study. Informed consent for CER is different from
informed consent for studies of previously untested therapies in at least three
important ways. First, in studies of new therapies, the potential harms are,
generally, not completely known. For a CER study, by contrast, all the